Article pubs.acs.org/joc
Total Synthesis of (+)-Sieboldine A: Evolution of a PinacolTerminated Cyclization Strategy Stephen M. Canham,† David J. France,‡ and Larry E. Overman* Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States S Supporting Information *
ABSTRACT: This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study, a number of pinacolterminated cationic cyclizations were examined to form the cishydrindanone core of sieboldine A. Of these, a mild Au(I)promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor.
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(IC50 1.6 μM), and also exhibited modest cytoxicity toward murine lymphoma L1210 cells (IC50 5.1 μg/mL).4 Motivated largely by its distinctive structure, (+)-sieboldine A (2) was selected as a worthy target for total synthesis. Sieboldine A contains an unprecedented N-hydroxyazacyclononane ring embedded in a bicyclo[5.2.1]decane-N,O-acetal, the fragment shown in red in Figure 1. These functionalities were previously unknown in natural products and in the chemical literature as a whole. Sieboldine A also contains a cishydrindane, the distinctive structural feature of the fawcettimine class of Lycopodium alkaloids.1 Herein, we describe the evolution of a synthetic sequence that culminated in the first total synthesis of (+)-sieboldine A (2) in 2010.5 In 2011, Tu and co-workers reported the total synthesis of (±)-alopecuridine and its conversion to (±)-sieboldine A by the biomimetic sequence first postulated by Kobayashi.4,6
INTRODUCTION The Lycopodium family of alkaloids displays a diverse array of complex molecular structures, which for years have served to stimulate innovation in organic synthesis.1 Although the biological profile of only a few alkaloids of this family has been studied in detail, several are known to exhibit important biological activities. Notably (−)-huperzine A (1), an acetylcholinesterase inhibitor, is currently undergoing clinical evaluation for the treatment of Alzheimer’s disease and schizophrenia (Figure 1).2,3
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RESULTS AND DISCUSSION Synthesis Plan. Our synthetic planning was influenced by the anticipated sensitivity of the hydroxylamine N,O-acetal functionality of sieboldine A (2). As a result, we envisaged forming the N-hydroxyazacyclononane ring at a late stage in the synthesis by intramolecular condensation of a tethered hydroxylamine side chain with the five-membered lactol 4 (X = OH) or a derivative (Scheme 1).7 Spirotricyclic tetrahydrofuran 4 was seen arising from α-methylene cis-hydrindandione 5 by conjugate addition of a two-carbon fragment, followed by oxidation of the resulting enolate or silyl derivative from the less-hindered convex face. Because of the many previous syntheses of Lycopodium alkaloids of the fawcettimine class,8 a variety of approaches for
Figure 1. Structure of (−)-huperizine A, (+)-sieboldine A, and (+)-alopecuridine and X-ray model4 of (+)-sieboldine A.
In 2003, Kobayashi and co-workers reported the isolation of (+)-sieboldine A (2) as a minor alkaloid of the Japanese club moss Lycopodium sieboldii together with the known alkaloid (+)-alopecuridine (3).4 Extensive NMR and single-crystal X-ray analysis secured the unprecedented structure of sieboldine A. This structurally unique Lycopodium alkaloid was reported to inhibit electric eel acetylcholinesterase with an IC50 value of 2.0 μM, which is comparable to that reported for (±)-huperzine A © XXXX American Chemical Society
Special Issue: Robert Ireland Memorial Issue Received: May 3, 2012
A
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Scheme 1. Initial Retrosynthetic Analysis of Sieboldine A
Scheme 2. Synthesis of Vinyl Iodide 13
low temperatures (−100 °C → −78 °C), provided a 1:1 ratio of adduct 15 to the cis-alkene resulting from protodeiondination of 13 (Scheme 3).16 To suppress competitive enolization, Scheme 3. Nucleophilic Addition to Cyclopentanone 14
forming the cis-hydrindanone portion of sieboldine A were conceivable. In earlier work from our laboratory, we had used a pinacol-terminated Prins cyclization to assemble this fragment in total syntheses of (−)-magellanine and (+)-magellaninone.9,10 We were attracted again to this strategy in the present context, envisaging cis-hydrindandione 6 as the direct precursor of α-methylene dione 5. If the alkoxymethyl side chain of the cyclopentane ring of 6 were to be introduced in a pinacol-terminated cyclization, the progenitor of cis-hydrindandione 6 would be an intermediate such as 7. This projected cascade sequence would examine for the first time whether an alkene π nucleophile containing two inductively deactivating allylic oxygen substituents would be viable in a Prins−pinacol transformation. As indicated in intermediates 7−9, the C15 methyl group could be incorporated at the outset, or potentially introduced after forming the cis-hydrindanone ring. Although several steps would be involved in introducing the C15 methyl group at the cis-hydrindanone stage, this strategy would allow the pivotal Prins−pinacol reaction (8 → 7) to be quickly examined. Our initial investigations pursued this strategy. Prins−Pinacol Rearrangement to Assemble the cisHydrindanone Core in the C15 Demethyl Series. As precursor 8 (R1 = H) should be readily available from the reaction of vinyl organometallic 10 and cyclopentanone 9 (R1 = H), synthesis of an appropriate vinyl iodide fragment 13 began with readily available 6-(tert-butyldiphenylsiloxy)-2-hexynoate (11).11 Stannylcupration of this ynoate, followed by quenching with MeOH at −78 °C, afforded vinylstannane 12 (>20:1 E/Z) in high yield (Scheme 2).12 Reduction of the methyl ester of 12, etherification of the resulting primary alcohol with phenol under Mitsunobu conditions,13 and stereospecific tin−halogen exchange gave (E)-vinyl iodide 13 in 68% overall yield from 11. This series of reactions could be carried out efficiently to access 13 on scales up to 60 g. Coupling of vinyl iodide 13 with cyclopentanone 1414 initially proved challenging. Using s-BuLi in the iodide−lithium exchange of iodide 13,15 followed by addition of ketone 14 at
(E)-vinyl iodide 13 was converted to the corresponding lithium reagent with 1.65 equiv of s-BuLi and added to a slurry of CeCl3 in THF at −78 °C. After formation of the vinylcerium species, ketone 14 was added at −78 °C to give tertiary allylic alcohol 15 in 81% yield. Addition of anhydrous LiCl to the cerium slurry, a procedure initially reported by Knochel,17 improved the yield of allylic alcohol 15 to 96% (>10:1 diastereoselectivity).18 Silylation of tertiary allylic alcohol 15 with TMS-imidazole and a catalytic amount of tetrabutylammonium fluoride (TBAF) provided the Prins−pinacol precursor 16 in 76% yield.19 The pivotal Prins−pinacol reaction of alkenyl acetal 16 was studied in detail (Scheme 4). Exposure of alkenyl acetal 16 to 0.9 equiv of BCl3, BF3·OEt2, or TMSOTf in CH2Cl2 at −78 °C and quenching the reaction at low temperature gave either a complex mixture of products or largely bicyclic acetal 17 resulting from desilylation of 16. However, in the presence of 0.9 equiv of SnCl4 (in CH2Cl2 at −78 °C → 0 °C), precursor 16 provided cis-hydrindanone 19, a 5.6:1 mixture of α:β methoxy epimers, in 51% yield together with 25% of a lesspolar byproduct. Upon isolation, this byproduct was shown to be the Prins cyclization product 18; particularly diagnostic were signals for the allylic methine and methylene hydrogens between 4.20 and 4.63 ppm. Hydrindene 18 would arise from deprotonation of the axial β-hydrogen of tertiary carbocation intermediate B prior to the desired semipinacol shift to give Prins−pinacol product 19. The formation of Prins cyclization byproducts similar to hydrindene B
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Scheme 4. Prins−Pinacol Rearrangement To Form the cisHydrindanone Core
Table 1. Lewis Acid Activation of Dimethyl Acetal 16 entry
conditionsa
18/19b
1
BCl3, CH2Cl2, −78 °C
nd
2 3 4 5
BF3·OEt2, CH2Cl2, −78 °C TMSOTf, CH2Cl2, −78 °C SnCl4, CH2Cl2, −78 °C → −20 °C SnCl4, MeNO2, 0 °C
nd nd 1.0:2.0 nd
6 7
SnCl4, i-PrNO2, −78 °C → −20 °C TiCl4, CH2Cl2, −78 °C → −20 °C
1.0:2.8 10:1 ratio (Table 3, entry 8). Computational studies by Toste, Goddard, et al. have suggested that the steric size of the 2-(di-tert-butylphosphino)biphenyl ligand inhibits back-bonding stabilization between the metal center and the alkyne, effectively increasing the carbocationic nature of the gold alkyne species.75,76 In the present case, the reduced Au-dπ to C-pπ orbital overlap likely favors cationic olefin cyclization over the heterocyclization pathway.77 The Au(I)-initiated cascade 71 → 72 was readily scalable to a gram-scale reaction providing cis-hydrindanone 72 in 84% yield (Table 3, entry 9). Completion of the Total Synthesis of (+)-Sieboldine A. With access to gram quantities of enantioenriched cishydrindanone 72 in hand, we turned to see if the chemistry defined in the C15 demethyl series would allow (+)-sieboldine A to be prepared in a straightforward fashion. Fortunately, that proved to be the case with one important modification (Scheme 19). The final elaboration to sieboldine A began by oxidative cleavage of the exomethylene group of 72 by ozonolysis, a transformation that required careful monitoring to prevent the formation of overoxidation products. After quenching the ozonide with dimethyl sulfide at −78 °C and allowing the reaction to warm to room temperature overnight, a solvent swap from CH2Cl2 to acetonitrile, followed by addition of 1.2 equiv of DBU at 0 °C to the crude diketone, delivered methylene enone 74 in 75% yield from 72. Cyclocondensation of enone 74 with ethyl vinyl ether afforded dihydropyran 75 in 86% yield.30 Selective reduction of the C13 carbonyl of tricyclic intermediate 75 with DIBALH in CH2Cl2 at −78 °C, followed by epoxidation of the dihydropyran with 1.2 equiv of dimethyldioxirane (DMDO) in CH2Cl2 at 0 °C, gave rise to I
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Scheme 19. Elaboration of cis-Hydrindanone 72 to Thioglycoside Intermediate 77
Scheme 18. Au(I)-Catalyzed Pinacol-Terminated 1,6-Enyne Cyclization
intermediate 35, Scheme 8) with TFA/H2O/THF (1:1:3) were low yielding and plagued by partial cleavage of the TBDPS group. Thioglycosides are commonly utilized in carbohydrate chemistry to form bonds at the anomeric carbon and are activated under a variety of mild reaction conditions.78 With this in mind, the mixture of ethoxy epimers formed from DMDO oxidation of 75 was redissolved in CH2Cl2 containing 5 equiv of EtSH, cooled to −78 °C, and exposed to 1.1 equiv of BF3·OEt2 to give thioglycoside 76 in 53% yield (Scheme 19).79 Removal of the TBDPS group of 76 with 3 equiv of TBAF in THF, coupling with N-(methoxymethoxy)-2-nitrobenzenesulfonamide under Mitsunobu conditions,80 and removal of the nosyl group provided intermediate 77. Several conditions were examined for forming the final azacyclononane ring from thioglycoside precursor 77 (Table 4). Exposure of 77 to mercury or silver salts, tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA),81 or p-nitrobenzenesulfenyl triflate (NO2PhSOTf)82 provided product 78 harboring the desired N-alkoxyazacyclononane ring in low
a tricyclic dihydropyran intermediate as a 1:1 mixture of ethoxy epimers. Initial attempts to convert this intermediate to the corresponding dilactol (i.e., the C15 methyl analogue of Table 3. Au(I) Catalysts and Selectivity for PinacolTerminated 1,6-Enyne Cyclization conditionsa
entry 1 2 3 4 5 6 7 8 9
10 10 10 10 10 10 10 10 10
mol mol mol mol mol mol mol mol mol
% % % % % % % % %
[Au(PPh3)]3OBF4 PPh3AuClb Me3PAuClb Et3PAuClb μ-(Ph2P)2CH2Au2Cl2c t-Bu3PAuClb (NHC)AuClb [(t-Bu)2P(o-biphenyl)]AuClb [(t-Bu)2P(o-biphenyl)]AuClb,d
Table 4. Activation Conditions for Formation of the NAlkoxyazacyclononane Ring
yield (72/73) NR 94% 90% 91% 85% 88% 89% 95% 84%
(1:1) (1.5:1) (2:1) (2:1) (2.5:1) (3:1) (10:1) (13:1)
a
entry
conditionsa
yield
1 2 3 4 5 6 7
NO2PhSOTf, DTBMP, 4 Å MS, CH2Cl2, −78 °C HgCl2, CaCO3, 4 Å MS, CH2Cl2, rt TBPA, 4 Å MS, CH3CN AgPF6, DTBMP, 4 Å MS, CH2Cl2, 0 °C DMTST, DTBMP, 4 Å MS, CH2Cl2, 0 °C DMTST, DTBMP, 4 Å MS, CH2Cl2, 0 °C, inverse addition DMTST, DTBMP, 4 Å MS, CH3CN, −20 °C, inverse addition
10% 16% 18% 28% 37% 42% 51%
a DTBMP = 2,6-di-tert-butyl-4-methylpyridine. TBPA = tris(4bromophenyl)ammoniumyl hexachloroantimonate. DMTST = dimethyl(metylthio)sulfonium triflate.
All reactions were carried out on a 0.03 mmol scale at 0.05 M in CH2Cl2 with 1.1 equiv of i-PrOH at rt. b5 mol % AgSbF6. c9 mol % AgSbF6. dConducted on 3.2 mmol scale; NR = no reaction. J
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yields, 10−28% (Table 4, entries 1−4). Activation of thioglycoside 77 with 5 equiv of dimethyl(methylthio)sulfonium triflate (DMTST)83,84 in CH2Cl2 (0.009 M) at 0 °C was somewhat better, giving 78 in 37% yield (Table 4, entry 5). The cyclization was further improved by slow addition of thioglycoside 77 to a solution of 5 equiv of DMTST in MeCN (0.009 M) at −20 °C, which delivered pentacyclic intermediate 78 in a notable 51% yield (Table 4, entry 7).
EXPERIMENTAL SECTION
Experimental procedures and characterization data for the preparation of vinyl iodide 13, N-(methoxymethoxy)-2-nitrobenzenesulfonamide, and compounds 60−65, 71−79, and 2 have been reported previously.5 General Procedure for Adding Vinylcerium Reagents to Cyclopentanone Intermeiates. Preparation of (1*S,2S*)-1-((E)6-(tert-Butyldiphenylsilyloxy)-1-phenoxyhex-2-en-3-yl)-2-(2,2dimethoxyethyl)cyclopentanol (15). A cyclohexane solution of sBuLi (13.3 mL, 12.9 mmol, 0.97 M, 1.65 equiv)87 was added dropwise to THF (26 mL) at −78 °C, forming a clear bright yellow solution. A solution of vinyl iodide 135 (6.50 g, 11.7 mmol, 1.50 equiv) and THF (8.5 mL) was added dropwise; the internal temperature was monitored during the addition to ensure that the temperature did not exceed −50 °C. After the addition, the solution was stirred at −78 °C for 15 min. In a separate flask, a previously prepared slurry of anhydrous CeCl3 (4.41 g, 17.9 mmol, 1.70 equiv),88 anhydrous LiCl (1.12 g, 26.5 mmol, 3.40 equiv), and THF (39 mL) was cooled to −78 °C and a cyclohexane solution of s-BuLi was added dropwise until a pale yellow color persisted (ca. 1.0 mL). The vinyllithium species was cannulated to the CeCl3·2LiCl slurry, producing an orange suspension, which was stirred at −78 °C for 30 min. A solution of cyclopentanone 1414 (1.34 g, 7.79 mmol, 1.00 equiv) and THF (8.5 mL) was then added dropwise, resulting in the disappearance of the orange color. The suspension was allowed to slowly warm to rt over 12 h. The solution was then partitioned between Et2O (100 mL) and 10% aq. AcOH (100 mL). The layers were separated, and the aqueous phase was extracted with Et2O (2 × 100 mL). The combined organic layers were washed with sat. aq. NaHCO3 (50 mL), followed by a wash with brine (30 mL). The organic phase was dried over MgSO4, filtered through a plug of cotton, and concentrated under reduced pressure. Purification by flash column chromatography (24:75:1 EtOAc/ hexanes/Et3N) afforded a 14:1 ratio of tertiary alcohol 15 and its (1S*,2R*) diasteromer (4.50 g, 96% yield) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.0, 1.4 Hz, 4H), 7.41 (t, J = 7.3 Hz, 2H), 7.36 (t, J = 7.5 Hz, 4H), 7.25 (t, J = 8.6 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 7.8 Hz, 2H), 5.90 (t, J = 6.3 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.38 (dd, J = 7.2, 4.2 Hz, 1H), 3.67 (t, J = 5.1 Hz, 2H), 3.28 (s, 3H), 3.25 (s, 3H), 2.26−2.20 (m, 1H), 2.17−2.11 (m, 1H), 2.05−1.99 (m, 1H), 1.95−1.91 (m, 2H), 1.87−1.83 (m, 1H), 1.76−1.69 (m, 2H), 1.67−1.57 (m, 4H), 1.52−1.47 (m, 1H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 158.8, 147.1, 135.6, 133.8, 129.7, 129.5, 127.7, 120.7, 120.5, 114.7, 104.0, 85.1, 65.0, 63.8, 52.8, 52.7, 42.7, 39.9, 33.6, 31.7, 30.1, 26.9, 25.1, 22.1, 19.3; IR (thin film) 3437, 2955, 2930, 1496, 1240, 1112 cm−1; HRMS-ESI (m/z) [M + Na]+ calcd for C37H50O5SiNa, 625.3325; found, 625.3318. tert-Butyl((E)-4-((1S*,2S*)-2-(2,2-dimethoxyethyl)-1(trimethylsilyloxy)cyclopentyl)-6-phenoxyhex-4-enyloxy)diphenylsilane (16). A solution of tetra-n-butylammonium fluoride in THF (0.17 mL, 0.17 mmol, 1.0 M, 0.01 equiv) was added dropwise to a solution of tertiary alcohol 15 (10.0 g, 17.0 mmol, 1.00 equiv), TMS-imidazole (5.1 mL, 35 mmol, 2.0 equiv), and DMF (44 mL) at rt. After 3 h, the solution was partitioned between water (500 mL) and Et2O (250 mL), the layers were separated, and the aqueous phase was extracted with Et2O (3 × 200 mL). The combined organic layers were washed with water (500 mL) and then brine (500 mL), dried over MgSO4, filtered through a plug of cotton, and concentrated under reduced pressure. Purification by flash chromatography (1:10:89 Et3N/EtOAc/hexanes) afforded silyl ether 16 as a colorless oil (9.0 g, 76% yield): 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 7.9, 1.3 Hz, 4H), 7.42 (tt, J = 7.3, 2.0 Hz, 2H), 7.36 (t, J = 6.8 Hz, 4H), 7.24 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.87 (dd, J = 8.8, 1.0 Hz, 2H), 5.83 (t, J = 6.4 Hz, 1H), 4.59 (dd, J = 6.4, 2.9 Hz, 2H), 4.37 (dd, J = 7.6, 4.4 Hz, 1H), 3.69−3.64 (m, 2H), 3.29 (s, 3H), 3.21 (s, 3H), 2.26− 2.20 (m, 1H), 2.04−2.00 (m, 1H), 1.97−1.91 (m, 1H), 1.88−1.84 (m, 1H), 1.83−1.78 (m, 1H), 1.77−1.71 (m, 2H), 1.69−1.62 (m, 3H), 1.61−1.60 (m, 1H), 1.49−1.43 (m, 1H), 1.42−1.36 (m, 1H), 1.05 (s, 9H), 0.07 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 158.9, 145.6, 135.6, 133.8, 129.7, 129.4, 127.7, 121.9, 120.5, 114.8, 104.2, 88.1, 64.9, 63.8, 53.2, 51.7, 44.5, 36.4, 33.6, 30.9, 29.6, 26.9, 25.2, 22.1, 19.3, 2.0;
The total synthesis of (+)-sieboldine A was completed in two additional steps (Scheme 20). Oxidation of the cyclic Scheme 20. Completion of the Total Synthesis of Sieboldine A
hemiacetal unit of 78 with TPAP provided diketone 79 in 88% yield. The MOM ether of 79 could be removed to give (+)-sieboldine A, albeit in low yield (
